Cyclic peptoids have recently emerged as important examples of peptidomimetics for their interesting complexing properties and innate ability to permeate biological barriers. In the present contribution, experimental and theoretical data evidence the intricate conformational and stereochemical properties of five novel hexameric peptoids decorated with N-isopropyl, N-isobutyl, and N-benzyl substituents. Complexation studies by NMR, in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB), theoretical calculations, and single-crystal X-ray analyses indicate that the conformationally stable host/guest metal adducts display architectural ordering comparable to that of the enniatins and beauvericin mycotoxins. Similarly to the natural depsipeptides, the synthetic oligolactam analogues show a correlation between ion transport abilities in artificial liposomes and cytotoxic activity on human cancer cell lines. The reported results demonstrate that the versatile cyclic peptoid scaffold, for its remarkable conformational and complexing properties, can morphologically mimic related natural products and elicit powerful biological activities.

2‐Acetylbenzonitriles have been conveniently synthesized by the oxidation of the respective 2‐ethylbenzonitriles, combining in a one‐pot procedure radical bromination and hydrolysis reactions. The obtained ketones reacted under very mild conditions with carbon and hetero nucleophiles to give a wide range of 3,3‐disubstituted isoindolinones in yields of 80–99 % by a tandem process consisting of an addition step and a subsequent Dimroth‐type rearrangement. Among the tested nucleophiles, the addition of water in the presence of a catalytic amount of KOH allowed a convenient access to an unprecedented variety of novel 3‐hydroxy‐3‐methylisoindolinones.

Controlling the network of intramolecular interactions encoded by Nα-chiral side chains and the equilibria between cis-and trans-amide junctions in cyclic peptoid architectures constitutes a significant challenge for the construction of stable reverse turn and loop structures. In this contribution, we reveal, with the support of NMR spectroscopy, single-crystal X-ray crystallography and density functional theory calculations, the relevant noncovalent interactions stabilizing tri-, tetra-, hexa-, and octameric cyclic peptoids (as free hosts and host−guest complexes) with strategically positioned N-(S)-(1phenylethyl)/N-benzyl side chains, and how these interactions influence the backbone topological order. With the help of theoretical models and spectroscopic/diffractometric studies, we disclose new γ-/β-turn and loop structures present in α-peptoidbased macrocycles and classify them according ϕ, ψ, and ω torsion angles. In our endeavor to characterize emergent secondary structures, we solved the solid-state structure of the largest metallated cyclic peptoid ever reported, characterized by an unprecedented alternated cis/trans amide bond linkage. Overall, our results indicate that molecules endowed with different elements of asymmetry (central and conformational) provide new architectural elements of facile atroposelective construction and broad conformational stability as the minimalist scaffold for novel stereodefined peptidomimetic foldamers and topologically biased libraries necessary for future application of peptoids in all fields of science.

Dipeptides are convenient building blocks for supramolecular gel biomaterials that can be produced on a large scale at low cost and do not persist in the environment. In the case...

Cascade reactions of ortho -carbonyl-substituted benzonitriles with ((chloromethyl)sulfonyl)benzenes as pronucleophiles led to new isoindolin-1-ones with a tetrasubstituted C-3 position or to ( Z )-3-(sulfonyl-methylene)isoindolin-1-ones. The reactions start from readily available materials, are carried out under mild conditions, and do not require metal catalysis. Promoted only by the cheap and environmentally benign K 2 CO 3 as the base, up to six elemental steps can be combined in a single pot. Hence, a sequential one-pot cascade/β-elimination/alkylation furnished useful intermediates for the synthesis of aristolactam natural products. The observed selectivity and the mechanism were investigated by DFT studies.

Herein we report new methodologies for the synthesis of the challenging ketones 2‐cyanobenzophenones, based on Suzuki‐Miyaura type cross‐coupling reactions and very mild oxidation of 2‐benzylbenzonitriles. The investigation of the reactivity of the obtained ketones highlighted a very good electrophilicity in the presence of mild carbon‐ and hetero‐nucleophiles, allowing the synthesis of 3,3‐disubstituted isoindolin‐1‐ones. All the developed methodologies are highly efficient and tolerate combinations of functional groups present on both the aromatic rings.

Formation of stable porous frameworks based on cyclic peptoids can be triggered by strategic choice of appropriate side chains. In this contribution we demonstrate that substitution of distal propargyl side chains with methoxyethyl groups in a fully propargylated cyclic octamer peptoid (cyclo-(Npa)8 1) greatly improves the solid state stability inducing permanent one-dimensional porosity of the compound (cyclo-[(NPa)3(Nme)]2 2, Npa = N-(propargyl)­glycine, Nme = N-(methoxyethyl)­glycine). In both compounds the macrocycles align along the shortest cell axis to form tubes that are filled with guest molecules. In situ hydration and dehydration single crystal X-ray diffraction studies on compound 2 demonstrated the improved stability of the host framework. Hirshfeld surface analysis and lattice energy calculations, also supported by energy frameworks analysis, clarified the determinant packing motifs in the studied compounds explaining the improved stability in terms of architectural robustness. Methoxyethyl side chains act as H-bond acceptor by tightening as wall ties the host framework, at a difference with propargyl side chains that provide CH−π interactions with similar energy, but along a less effective direction.

Herein we report the first asymmetric Michael reaction of arylidene-isoxazol-5-one with 1,3-diesters. Despite complex tautomer equilibria of the obtained Michael adducts, the one-pot entrapping strategy by the aid of different electrophiles/ protecting groups led to the selective isolation of diverse N-substituted isoxazol-5-ones in very high overall yield and good enan-Eur.the obtaining of isoindoline based heterocyclic compounds via organocatalytic cascade reactions. [22][23][24][25] Continuing our efforts aiming to develop challenging asymmetric synthesis of complex heterocyclic architectures of isoxazol-5-one, [15] considering the importance to perform sequential reactions in one-pot fashion for atom and step economy, [26] herein we describe the first enantioselective Michael reaction of malonate diesters with arylideneisoxazol-5-ones 1 and the selective tautomer entrapping of the respective adducts with electrophiles. Asymmetric three component Michael/electrophilic tautomer entrapping and four-component Knoevenagel/Michael/electrophilic-tautomer entrapping one-pot protocols have also been investigated and the results have been critically compared.